In recent times it has become known that many chiral drug compounds which have a high degree of biological activity, in fact represent racemic mixtures of optical isomers, one isomer usually being highly active, and the others not nearly as active. In some cases, only one isomer is active. As this has been discovered, it has become more desirable to prepare certain known biologically active compounds by enantioselective synthesis. Put another way, a synthesis which would provide selectively in predominant form a high percentage of one isomer over another is now an important tool for the drug synthesis chemist.
Earlier work of Dr. Huw M. L. Davies, has reported on synthesizing biologically active tropane derivatives, see for example U.S. Pat. No. 5,262,428 issued Nov. 16, 1993 concerning tropane derivatives which may be described as cocaine analogs, useful as cocaine replacement drugs. Similarly, Davies, et al., U.S. Pat. No. 5,342,949, issued Aug. 30, 1994, describes a two-step process for preparing biologically active tropane derivatives. Finally, Davies, et al., U.S. Pat. No. 5,288,872, issued Feb. 22, 1994, describes compounds for treatment of neurodegenerative diseases that contain tropane rings. The disclosures of each of these earlier patents are incorporated herein by reference.
Since seven-membered carbocycles are known to be biologically active, and many are known to be chiral, it necessarily follows that it would be important to develop a chiral synthesis of these compounds. In an earlier report by Davies and Hutcheson, Tetrahedron Letters, Vol. 34, No. 45, pp. 7243-7246, 1993, Dr. Davies, et al. report an effective chiral catalyst for the asymmetric cyclopropanation of alkenes. In that process as there described, enantioselective transformations are prepared by rhodium(II)-N-(arenesulfonyl) prolinate catalyzed decomposition of vinyldiazomethanes in the presence of alkenes. The enantioselectivity reported there varies from 9% up to 95%.
Earlier work, however, has demonstrated that there is little predictability of the extension of work with one chiral catalyst to another system. Put another way, experience has shown that it is not at all predictable that a chiral catalyst used in a system as for example shown in the Tetrahedron Letters publication necessarily works in a different system.
In accordance with the present invention, and as a further improvement on the processes reported in the earlier Davies publications and patents, it has now been discovered that a highly stereoselective synthesis of seven-membered carbocycles will occur by reacting a diene with a vinyldiazomethane, in the presence of a non-polar solvent and a di-rhodium(II) tetra[N]-arylsulfonyl 1-aza-cycloalkane-2 carboxylate. Surprisingly, the amount of enantiomeric excess (% ee) in certain instances is as high as 90%, and reaction yields may go as high as 70% to 98%.
Accordingly, it is a primary object of the present invention to provide a simple stereoselective single-step synthesis of seven-membered carbocycles.
Another object of the present invention is to provide an enantioselective process of synthesizing chiral biologically active tropane ring containing compounds.
The method and means of accomplishing each of the above objectives will become apparent from the detailed description of the invention which follows hereinafter.